基于多药协同作用和逆转肿瘤耐药性的纳米药物载体的设计和构筑

This project was proposed to prepare a kind of amphiphilic block polymer, which was made up of lactide (LA), caprolactone (CL) as the main chain and different functional groups in its side chain. multiple chemotherapeutic drugs were conjugated to the different functional groups of the polymer and the amphiphilic polymer-drug conjugate was obtained carrying a variety of chemotherapeutic drugs. Hydrophobic P-glycoprotein (P-gp) inhibitor was encapsulated into the micelles formed by the self-assembly of the amphiphilic polymer-drug conjugate, eventually, a kind of nanomedicine carrier system was Prepared with reversing multidrug resistance(MDR)of tumor and multiple drugs synergistic effects. owing to entrapped into the micelles physically, P-gp inhibitor could be released earlier and faster than the chemotherapeutic drugs, and drugs could be simultaneously delivered to tumor region and Sequentially release. The self-assembly, drug release assessment in vitro should be studied. The cytotoxicity will also be conducted in vitro and vivo. Meanwhile, synergistic effects and reverse the MDR effect should be studied, which should contribute to discover the mechanism and the influencing factors. These insights should provide more basis and guidance toward the design and development of novel nanomedicine carriers and dosage system for anticancer application.

本项目提出制备一种以丙交酯（LA），己内酯（CL）嵌段聚合物为主链，在其侧链上引入不同官能团，在此基础上将多种化疗药物通过化学键合的方法，键接到聚合物的不同官能团上，得到载有多种化疗药物的两亲性高分子键合药。同时通过对两亲性高分子键合药进行自组装，把亲油性的P-糖蛋白抑制剂包载在纳米胶束的内腔里，最终制备一种具有逆转肿瘤耐药性和多药协同作用的纳米药物载体体系。由于是物理包裹在胶束的内腔，P-糖蛋白抑制剂比化疗药物的释放就会更早和更快，这样可以实现P-糖蛋白抑制剂和化疗药物同时被输送到肿瘤组织和他们的有序先后释放。通过对制备的纳米载药体系的自组装行为，模拟人体生理环境下的体外药物释放行为进行研究，以及体外细胞和体内细胞实验，对这载药体系的细胞毒性行为，协同效应和抑制耐药性效果进行研究，探讨其作用机理与影响因素，为进一步设计与制备新型纳米药物载体和给药体系提供依据和指导。

合成具有反应活性官能团的脂肪族聚酯，制备可降解的、具有亲水性和良好的生物相容性，具有逆转肿瘤耐药性和多药协同作用的纳米药物载体体系是本项目的主要目标。通过课题组的努力，我们制备了以阿霉素、紫杉醇、鬼臼毒素、康普瑞汀，咪喹莫特，替拉扎明为药物分子的多药聚合物前药，得到了多种具有多药协同作用和逆转肿瘤耐药性的纳米药物体系.，相应的细胞毒性测试表明我们制备的聚合物前药纳米体系对癌细胞有很好的多药协同效应，肿瘤耐药性得到了抑制。主要研究内容包括：（1）基于紫杉醇和阿霉素的具有双药协同作用的两亲性三嵌段高分子键合药的制备；（2）一锅煮法制备的具有多药协同作用的紫杉醇和阿霉素的两亲性聚合物前药；（3）具有细胞穿透能力和多药协同效应的智能型的高分子键合药的制备与表征；（4）具有 P-糖蛋白抑制作用的鬼臼毒素的聚合物前药的制备与表征；（5）刺激响应型鬼臼毒素聚合物前药的制备与表征；（6）具有协同效应的阿霉素和鬼臼毒素聚合物前药联合用药体系的研究；（7）血管阻断疗法-免疫疗法协同作用的高分子键合药的制备与表征；（8）基于血管阻断疗法和化疗协同作用的刺激响应性高分子键合药的制备与表征；（9）乏氧疗法-血管阻断疗法协同作用的高分子键合药的制备与表征。通过本项目的四年的实施，目前已发表标注基金资助的论文9篇，投稿3篇，申请中国专利10项，授权专利3项。在本项目的资助培养下，已有10名硕士研究生，1名博士研究生顺利毕业。